Oxcarbazepine (10-oxo-10,11-dihydro-5H-dibenz[b, f]azepine-5-carboxamide) of the general formula:
has valuable therapeutic benefits and acts as a central nervous system depressant. Currently it is being marketed as TRILEPTAL®, for treatment of epilepsy. According to the prescribing information for TRILEPTAL®, the pharmacological benefit of oxcarbazepine is primarily exerted through the 10-hydroxy metabolite of oxcarbazepine. In vitro studies indicate that the metabolite blocks voltage sensitive sodium channels, which results in the stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the brain. U.S. Pat. No. 5,658,900, incorporated herein by reference, further teaches the use of oxcarbazepine to treat Parkinson's disease. TRILEPTAL® is administered in a dosage units of 150 mg, 300 mg and 600 mg.
U.S. Pat. Nos. 3,716,640; 4,452,738; 4,559,174 and 5,808,058 are hereby incorporated by reference for their disclosures of processes for preparing oxcarbazepine.
The present invention relates to the solid state physical properties of oxcarbazepine prepared by any of the disclosed or other methods. These properties can be influenced by controlling the conditions under which the oxcarbazepine is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular crystalline form of a substance. The crystalline form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry.
According to U.S. Pat. No. 3,716,640, oxcarbazepine may be prepared from 10-methoxy-5H-dibenz[b, f]azepine-5-carboxamide of formula:
by hydrolysis with hydrochloric acid. Oxcarbazepine with a melting point of 215–216° C. was obtained after recrystallization from ethanol.
U.S. Pat. No. 4,559,174 contains numerous examples of a process of preparing oxcarbazepine via a 5-cyano-10-nitro-5H-dibenz[b,f]acepine intermediate. In these examples, the product was obtained as a precipitate from the mother liquor and in some instances recrystallized and in other instances washed or slurried with solvent to remove impurities. Solvents from which oxcarbazepine was precipitated or recrystallized are chlorobenzene, acetic acid/water, water, isopropanol, acetonitrile and methanol/water.
U.S. Pat. No. 5,808,058 teaches that oxcarbazepine may be prepared from N-carbamoylization of 10-methoxyminostilbene with sodium or potassium cyanate in the presence of a strong non-aqueous acid, followed by mild aqueous acid hydrolysis of the methoxy group. In the examples, oxcarbazepine was recrystallized from dimethylacetamide, cyclohexanone, ethylcellosolve, 2:1 DMF:water, methanol and dioxane.
The oxcarbazepine that is formulated into the commercial product TRILEPTAL® is designated herein as oxcarbazepine Form A. Oxcarbazepine Form A is a white to faintly orange crystalline powder. It is slightly soluble in solvents such as chloroform, dichloromethane, acetone and methanol, and practically insoluble in solvents ethanol, ether and water. Due to its low solubility, crystallization of oxcarbazepine from water is impracticable unless the crystallization is carried on from a hot solution. Crystallization from water and various organic solvents such as acetonitrile, THF, ethyl acetate, EtOH/toluene, dichloromethane, DMA, DMF, cyclohexane, cyclohexanone, alcohols, chloroform, water/DMA, DMA/hexane, DMF/EtOH, DMA, and acetone consistently produce the prior art Form A.
There is a need for discovery of accessible but previously unknown polymorphic forms of a pharmaceutically useful compound because it provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Four new polymorphic and pseudopolymorphic forms of oxcarbazepine have now been discovered. They can be differentiated by their powder X-ray diffraction (“PXRD”) patterns and thermogravimetric analysis (“TGA”).